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Annals of surgical oncology
Jun, 2022;29 (6): 3405-3417.

Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

Marco Tonello, Dario Baratti, Paolo Sammartino, Andrea Di Giorgio, Manuela Robella, Cinzia Sassaroli, Massimo Framarini, Mario Valle, Antonio Macrì, Luigina Graziosi, Federico Coccolini, Piero Vincenzo Lippolis, Roberta Gelmini, Marcello Deraco, Daniele Biacchi, Francesco Santullo, Marco Vaira, Katia Di Lauro, Fabrizio D'Acapito, Fabio Carboni, Giuseppe Giuffrè, Annibale Donini, Paola Fugazzola, Pinuccia Faviana, Lorena Sorrentino, Antonio Scapinello, Paola Del Bianco, Antonio Sommariva
Author Information
  1. Marco Tonello: Unit of Surgical Oncology of the Esophagus and Digestive Tract, Surgical Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  2. Dario Baratti: Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  3. Paolo Sammartino: Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy.
  4. Andrea Di Giorgio: Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
  5. Manuela Robella: Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
  6. Cinzia Sassaroli: Colorectal Surgical Oncology, Abdominal Oncology Department, Fondazione Giovanni Pascale" IRCCS, Naples, Italy.
  7. Massimo Framarini: General and Oncologic Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy.
  8. Mario Valle: Peritoneal Malignancies Unit, INT "Regina Elena", Rome, Italy.
  9. Antonio Macrì: Peritoneal Surface Malignancy and Soft Tissue Sarcoma Program, University of Messina, Messina, Italy.
  10. Luigina Graziosi: General and Emergency Surgery Department, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
  11. Federico Coccolini: General Emergency and Trauma Surgery, Bufalini Hospital, Cesena, Italy.
  12. Piero Vincenzo Lippolis: General and Peritoneal Surgery, Department of Surgery, Hospital University Pisa (AOUP), Pisa, Italy.
  13. Roberta Gelmini: General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia, Modena, Italy.
  14. Marcello Deraco: Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  15. Daniele Biacchi: Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy.
  16. Francesco Santullo: Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
  17. Marco Vaira: Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
  18. Katia Di Lauro: Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy.
  19. Fabrizio D'Acapito: General and Oncologic Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy.
  20. Fabio Carboni: Peritoneal Malignancies Unit, INT "Regina Elena", Rome, Italy.
  21. Giuseppe Giuffrè: Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Section of Pathology, University of Messina, Messina, Italy.
  22. Annibale Donini: General and Emergency Surgery Department, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.
  23. Paola Fugazzola: General Emergency and Trauma Surgery, Bufalini Hospital, Cesena, Italy.
  24. Pinuccia Faviana: Pathological Anatomy III, Laboratory Medicine Department, Hospital University Pisa (AOUP), Pisa, Italy.
  25. Lorena Sorrentino: General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia, Modena, Italy.
  26. Antonio Scapinello: Pathology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  27. Paola Del Bianco: Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  28. Antonio Sommariva: Unit of Surgical Oncology of the Esophagus and Digestive Tract, Surgical Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. antonio.sommariva@iov.veneto.it.
PMID: 34783946 DOI: 10.1245/s10434-021-11045-3

Abstract

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.
METHODS: Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).
RESULTS: The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.
CONCLUSION: For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

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MeSH Term

Colorectal Neoplasms
Combined Modality Therapy
Cytoreduction Surgical Procedures
Humans
Hyperthermia, Induced
Hyperthermic Intraperitoneal Chemotherapy
Microsatellite Instability
Microsatellite Repeats
Peritoneal Neoplasms
Prognosis
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins p21(ras)
Retrospective Studies
Survival Rate

Chemicals

Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins p21(ras)
Journal Article
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Created with Highcharts 10.0.0patientssurvivalOS0HRstatusmonthsDFSp=CRSmicro-satelliteMSmutationsCI265-yearCytoreductiveHIPECperitonealPMstudyRAS/RAFtreated13Italianpathologicmedian95%5clinicalrelated4%vsMSIMSSMSI/WTprognosisPeritoneal14BACKGROUND:surgeryhyperthermicintraperitonealchemotherapyleadsprolongedselectedcolorectalCRCmetastasesaimedanalyzeprognosticroleMETHODS:DatacollectedcentersexpertisewithincollaborativegroupSocietySurgicalOncologyClinicalvariablesKRAS/NRAS/BRAFmutationalcorrelatedoveralldisease-freeRESULTS:enrolled437CRS-HIPEC423[95%confidenceinterval334-51months]123-149local20164-24additionknownfactorsKRAS005BRAF0104KRAS-BRAF-mutatedshorterwild-typeWT29268%515%respectivelyinstabilitylongerstability583%367%bestMSS/WTMSI/mutatedsimilarsurvivalswhereasMSS/mutatedshowedworst706%481%230001multivariableanalysisCancerIndex[hazardratio05perpoint]completenesscytoreductionCCscore8Nsignet-ringMSS/WT-MSI/mutationSimilarresultsobtainedCONCLUSION:affectedCRC-PMeligiblecriterianeedintegratedmolecularfeaturesKRAS/BRAFmutationMicro-satellitestronglyconsideredconfersadvantageevenmutatedMicrosatelliteMutationalStatusPrognosticFactorsColorectalMetastasesTreatedSurgeryHyperthermicIntraperitonealChemotherapy

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